The blood-brain barrier.

The concept of a blood-brain barrier (BBB) dates back to experiments performed by Paul Ehrlich. Using "intravital tracers" which change their color depending on their oxidative state, he intended to estimate the oxygen consumption of the bodily organs. An important prerequisite of this approach, however, would have been an equal distribution of these tracers at the beginning of the experiment, but this was not what he found: Hydrophilic dyes uniformly did not reach the parenchyma, which led his student, the Berlin physician Lewandowski to claim that the capillary wall provides a barrier for certain molecules in the brain, but it was not before the golden era of electron microscopy that Reese and Karnovsky detected what they called "morphological barriers" of the BBB. In this article, we provide an overview of what maintains barrier function for blood-molecules, clarify that a BBB for solutes is neither mechanistically equal to a barrier for immune cells nor in regard to the sites of entry (capillaries versus post-capillary venules), formulate areas of lack of knowledge and consequently, raise open questions to be addressed in the future.